A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency
Authors: Oriol Fornes, Alicia Jia, Hye Sun Kuehn, Qing Min, Ulrich Pannicke, Nikolai Schleussner, Romane Thouenon, Zhijia Yu, María de los Angeles Astbury, Catherine M. Biggs, Miguel Galicchio, Jorge Alberto Garcia-Campos, Silvina Gismondi, Guadalupe Gonzalez Villarreal, Kyla J. Hildebrand, Manfred Hönig, Jia Hou, Despina Moshous, Stefania Pittaluga, Xiaowen Qian, Jacob Rozmus, Ansgar S. Schulz, Aidé Tamara Staines-Boone, Bijun Sun, Jinqiao Sun, Schauer Uwe, Edna Venegas-Montoya, Wenjie Wang, Xiaochuan Wang, Wenjing Ying, Xiaowen Zhai, Qinhua Zhou, Altuna Akalin, Isabelle André, Thomas F. E. Barth, Bernd Baumann, Anne Brüstle, Gaetan Burgio, Jacinta C. Bustamante, Jean-Laurent Casanova, Marco G. Casarotto, Marina Cavazzana, Loïc Chentout, Ian A. Cockburn, Mariantonia Costanza, Chaoqun Cui, Oliver Daumke, Kate L. Del Bel, Hermann Eibel, Xiaoqian Feng, Vedran Franke, J. Christof M. Gebhardt, Andrea Götz, Stephan Grunwald, Bénédicte Hoareau, Timothy R. Hughes, Eva-Maria Jacobsen, Martin Janz, Arttu Jolma, Chantal Lagresle-Peyrou, Nannan Lai, Yaxuan Li, Susan Lin, Henry Y. Lu, Saul O. Lugo-Reyes, Xin Meng, Peter Möller, Nidia Moreno-Corona, Julie E. Niemela, Gherman Novakovsky, Jareb J. Perez-Caraballo, Capucine Picard, Lucie Poggi, Maria-Emilia Puig-Lombardi, Katrina L. Randall, Anja Reisser, Yohann Schmitt, Sandali Seneviratne, Mehul Sharma, Jennifer Stoddard, Srinivasan Sundararaj, Harry Sutton, Linh Q. Tran, Ying Wang, Wyeth W. Wasserman, Zichao Wen, Wiebke Winkler, Ermeng Xiong, Ally W. H. Yang, Meiping Yu, Lumin Zhang, Hai Zhang, Qian Zhao, Xin Zhen, Anselm Enders, Sven Kracker, Ruben Martinez-Barricarte, Stephan Mathas, Sergio D. Rosenzweig, Klaus Schwarz, Stuart E. Turvey, Ji-Yang Wang
Journal: Science Immunology (2023)

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii , and presented with agammaglobulinemia. Patients’ B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced T H 17 and T FH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4 T95R variant maps to the TF’s DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4 T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4 WT . Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4 T95R . Simultaneously, IRF4 T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4 T95R but not by IRF4 WT . This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.